Context. Palliative care remains suboptimal in end-stage liver disease (ESLD). Objectives. We report qualitative outcomes from the REDUCe study. We aimed to explore and contrast experiences/ perceptions/care pathways of patients with refractory ascites due to ESLD randomized to either palliative long-term abdominal drains (LTADs) (allow home drainage) vs. large volume paracentesis (LVP) (hospital drainage). Methods. Concurrent embedded qualitative study in a 12-week feasibility randomized controlled trial. Telephone interviews were conducted, data being recorded, transcribed verbatim, and analyzed using applied thematic analysis, considered in terms of a pathway approach toward accessing health care. Quantitative outcomes were collected (integrated palliative outcome scale, short-form liver disease quality of life, EQ-5D-5 L, Zarit Burden Interview-12). Results. Fourteen patients (six allocated LTAD and eight LVP) and eight nurses participated in the qualitative study. The patient journey in the LVP group could be hindered by challenges along the entire care pathway, from recognizing the need for drainage to a lengthy wait in hospital for drainage and/or to be discharged. These issues also impacted upon caregivers. In contrast, LTADs appeared to transform this care pathway at all levels across the patient's journey by removing the need for hospital drainage. Additional benefits included personalized care, improved symptom control of ascites, being at home, and regular support from community nurses. Nurses also viewed the LTAD favorably, though expressed the need for additional support should this become standard of care. Conclusion. Patients and nurses expressed acceptability of palliative LTAD in ESLD and preference for this approach in enabling care at home. Proceeding to a definitive trial is feasible. Trial registration. ISRCTN30697116, date assigned: 07/10/2015. J Pain Symptom Manage 2021;62:312e325. (c) 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

SummaryBackgroundPalliative care remains suboptimal in end‐stage liver disease.AimTo inform a definitive study, we assessed palliative long‐term abdominal drains in end‐stage liver disease to determine recruitment, attrition, safety/potential effectiveness, questionnaires/interview uptake/completion and make a preliminary cost comparison.MethodsA 12‐week feasibility nonblinded randomised controlled trial comparing large‐volume paracentesis vs long‐term abdominal drains in refractory ascites due to end‐stage liver disease with fortnightly home visits for clinical/questionnaire‐based assessments. Study success criteria were attrition not >50%, <10% long‐term abdominal drain removal due to complications, the long‐term abdominal drain group to spend <50% ascites‐related study time in hospital vs large‐volume paracentesis group and 80% questionnaire/interview uptake/completion.ResultsOf 59 eligible patients, 36 (61%) were randomised, 17 to long‐term abdominal drain and 19 to large‐volume paracentesis. Following randomisation, median number (IQR) of hospital ascitic drains (long‐term abdominal drain group vs large‐volume paracentesis group) were 0 (0‐1) vs 4 (3‐7); week 12 serum albumin (g/L) and serum creatinine (μmol/L) were 29 (26.5‐32.5) vs 30 (25‐35) and 104.5 (81‐115.5) vs 127 (63‐158) respectively. Total attrition was 42% (long‐term abdominal drain group 47%, large‐volume paracentesis group 37%). Median (IQR) fortnightly community/hospital/social care ascites‐related costs and percentage study time in hospital were lower in the long‐term abdominal drain group, £329 (253‐580) vs £843 (603‐1060) and 0% (0‐0.74) vs 2.75% (2.35‐3.84) respectively. Self‐limiting cellulitis/leakage occurred in 41% (7/17) in the long‐term abdominal drain group vs 11% (2/19) in the large‐volume paracentesis group; peritonitis incidence was 6% (1/17) vs 11% (2/19) respectively. Questionnaires/interview uptake/completion were ≥80%; interviews indicated that long‐term abdominal drains could transform the care pathway.ConclusionsThe REDUCe study demonstrates feasibility with preliminary evidence of long‐term abdominal drain acceptability/effectiveness/safety and reduction in health resource utilisation.Trial registration: ISRCTN30697116, date assigned: 07/10/2015.

Background and aims: Ascites develops in about 90% with advanced cirrhosis; when refractory to medical therapy, standard of care is repeated large volume paracentesis (LVP) with albumin support. Refractory ascites (RA) confers a median life expectancy of six months without liver transplantation (LT). LVP is not an optimal palliative strategy. One alternative is long-term abdominal drains (LTAD), used in advanced malignant ascites, also enabling community management. Our ultimate aim is to improve end of life care (EoLC) in advanced cirrhosis and RA. This feasibility randomised controlled trial (RCT) aimed to resolve uncertainties in designing a definitive RCT. Method: Multicentre feasibility RCT with 1:1 randomisation between standard of care (LVP) vs. LTAD (Rocket Medical) in adults with RA, ineligible for LT. Both arms received prophylactic antibiotics. LTAD were inserted under ultrasound guidance. Community nurses undertook home visits to drain ascites dependent on symptoms; (maximum 6L/week), without albumin support. Follow-up was 12 weeks with home visits every two weeks for the following assessments: clinical, questionnaire based to include quality of life, palliative care needs, carer burden and health economics (HE). Here we report clinical and HE outcomes. Results: Thirty six patients were randomised; 19 LVP (two withdrew, wanting LTAD) and 17 LTAD (one withdrew-insufficient ascites). Mean age (years) LTAD vs. LVP 66 + 10.4 vs. 68 ± 12; predominately male (76% vs. 74%). Participants were well matched at baseline in liver tests and prognostic scores: LTAD vs. LVP (serum bilirubin (μmol/L) 26 ± 15.8 vs. 16 ±10, serum albumin (g/L) 33 ± 4.2 vs. 31 ± 3.3, serum creatinine (mmol/L) 113 ± 46.7 vs.118 ± 53.1; MELD 14 ± 4.6 vs. 16 ± 7.2). One LTAD participant required hospitalisation for repeated LVP. Serum albumin (g/L) in the LTAD arm declined to 29 ± 3.3 at week two, subsequently remaining stable LTAD vs. LVP (29 ± 5.6 vs. 31 ± 5.5). Serum creatinine remained stable in both arms. There were no LTAD related serious adverse reactions. LTAD related adverse reactions included mild cellulitis (n = 4) and small volume leakage around LTAD insertion site (n = 3), all resolving rapidly. Peritonitis was rare, LTAD (possible) n = 1 and LVP n = 2. Overall mortality was 36% (12/33). Mortality and median survival (days in those who died) were 7/16 (44%) vs. 5/17 (29%), 53 days (IQR 43) vs. 61 days (IQR 35) in LTAD vs. LVP respectively. All but one death was liver related. Those in LTAD arm spent ≈20% less time in hospital. All nine alive in the LTAD arm at end of study elected to keep LTAD in. Detailed clinical and HE analysis is underway. Conclusion: Preliminary data from the REDUCe study supports the safety and efficacy of palliative LTAD in RA due to advanced cirrhosis. LTAD allows successful management in the community with reduction in health resource utilisation. Proceeding to a definitive RCT is justified.

Introduction Ascites develops in about 90% with advanced cirrhosis; when refractory to medical therapy, standard of care is repeated large volume paracentesis (LVP) with albumin support. Refractory ascites (RA) confers a median life expectancy of six months without liver transplantation (LT). LVP is not an optimal palliative strategy. One alternative is long-term abdominal drains (LTAD), used in advanced malignant ascites, also enabling community management. Our ultimate aim is to improve end of life care (EoLC) in advanced cirrhosis and RA. This feasibility randomised controlled trial (RCT) aimed to resolve uncertainties in designing a definitive RCT. Methods Multicentre feasibility RCT with 1:1 randomisation between standard of care (LVP) vs. LTAD (Rocket Medical) in adults with RA, ineligible for LT. Both arms received prophylactic antibiotics. LTAD were inserted under ultrasound guidance. Community nurses undertook home visits to drain ascites dependent on symptoms; (maximum 6L/week), without albumin support. Follow up was 12 weeks with home visits every two weeks for the following assessments: clinical, questionnaire based to include quality of life, palliative care needs, carer burden and health economics (HE). Here we report clinical and HE outcomes. Results Thirty six patients were randomised; 19 LVP (two withdrew, wanting LTAD) and 17 LTAD (one withdrew - insufficient ascites). Mean age (years) LTAD vs. LVP 66 ± 10.4 vs. 68 ± 12; predominately male (76% vs. 74%). Participants were well matched at baseline in liver tests and prognostic scores: LTAD vs. LVP (serum bilirubin (μmol/L) 26 ± 15.8 vs. 16 ±10, serum albumin (g/L) 33 ± 4.2 vs. 31 ± 3.3, serum creatinine (mmol/L) 113 ± 46.7 vs.118 ± 53.1; MELD 14 ± 4.6 vs. 16 ± 7.2). One LTAD participant required hospitalisation for repeated LVP. Serum albumin (g/L) in the LTAD arm declined to 29 ± 3.3 at week two, subsequently remaining stable LTAD vs. LVP (29 ± 5.6 vs. 31 ± 5.5). Serum creatinine remained stable in both arms. There were no LTAD related serious adverse reactions. LTAD related adverse reactions included mild cellulitis (n=4) and small volume leakage around LTAD insertion site (n=3), all resolving rapidly. Peritonitis was rare, LTAD (possible) n=1 and LVP n=2. Overall mortality was 36% (12/33). Mortality and median survival (days in those who died) were 7/16 (44%) vs. 5/17 (29%), 53 days (IQR 43) vs. 61 days (IQR 35) in LTAD vs. LVP respectively. All but one death was liver related. Those in LTAD arm spent ≈20% less time in hospital. All nine alive in the LTAD arm at end of study elected to keep LTAD in. Detailed clinical and HE analysis is underway. Conclusions Preliminary data from the REDUCe study supports the safety and efficacy of palliative LTAD in RA due to advanced cirrhosis. LTAD allows successful management in the community with reduction in health resource utilisation. Proceeding to a definitive RCT is justified.

Following publication of the original article [1], the authors reported that the figure legend for Figure 3 was absent. In addition, they have requested additional funding information to be added. In this Correction the initial and updated funding information are shown. The original publication of this article has been corrected.

Background: Ascites, the commonest complication of cirrhosis, leads to frequent hospitalisations. Refractory ascites confers a median survival of 6 months without liver transplantation. In many, the management remains palliative (large-volume paracentesis). Despite calls for improvement, palliative and end-of-life care is not yet integrated into end-stage liver disease. Long-term abdominal drains are a palliative strategy in malignant ascites, but not end-stage liver disease. Case presentation: A retrospective, single centre, case series review was performed of patients undergoing long-term abdominal drain placement for refractory ascites secondary to end-stage liver disease at a large teaching hospital between August 2011 and March 2013. Case management: Patients with end-stage liver disease and refractory ascites, where liver transplantation was not an option, were considered for long-term abdominal drains. Seven patients underwent successful long-term abdominal drain insertion after multi-professional assessment. Case outcome: Following long-term abdominal drain insertion, mean hospital attendances reduced to 1 (0–4) from 9 (4–21), with none for ascites management. Median survival after long-term abdominal drain insertion was 29 days (8–219). The complication rate was low and none life threatening. Conclusion: Palliative and end-of-life care needs in end-stage liver disease remain under-addressed. Our data suggest that long-term abdominal drains may be a safe and effective palliative intervention in end-stage liver disease. Prospective randomised controlled trials comparing large-volume paracentesis versus long-term abdominal drains in refractory ascites secondary to end-stage liver disease are warranted.

Multiple genetic and environmental factors interact to determine an individual's predisposition to non-alcoholic fatty liver disease and its phenotypic characteristics. Association studies have found a number of alleles associated with the development of non-alcoholic steatohepatitis. Our aim was to investigate whether multiple risk-associated alleles may be present in affected monozygotic twins, indicating underlying genetic predisposition to non-alcoholic steatohepatitis. We determined the genotype of 14 candidate gene polymorphisms (at 11 unlinked loci) in a set of monozygotic twins who presented with cirrhosis within 18 months of each other. Genotyping revealed multiple single nucleotide polymorphisms at 9 independent loci in genes PNPLA3, APOC3, GCKR, TRIB1, LYPLAL1, PPP1R3B, COL13A1, and EFCAB4B, previously implicated in contributing to non-alcoholic steatohepatitis pathogenesis. In conclusion, this case series illustrates the potential cumulative effect of multiple polymorphisms in the development and potential progression of a complex trait such as NASH cirrhosis.

#### Key learning points 'Cocoon syndrome' is a possible differential in patients with end-stage cirrhosis who present with vomiting and abdominal symptoms. Recurrent inflammation of the peritoneum from spontaneous bacterial peritonitis (SBP) leads to encasement of the bowel. Computed

Background/aims: We aimed to assess characteristics of patients with a positive hepatitis E virus serology with emphasis on acute on chronic liver disease.Methods: This was a retrospective audit performed at a large teaching hospital.Results: Of the 164 patients tested, 15(9.1%) had a positive serology (hepatitis E virus IgG and or IgM) of whom two also had a positive hepatitis E virus RNA. Six (42.8%) had underlying chronic liver disease and presented with deteriorating liver tests +/- decompensation. In one patient (16%) acute hepatitis E virus infection was the aetiology for the decompensation and in three the positive hepatitis E virus IgG was a reflection of prior subclinical infection. However, in two of the six patients with unexplained decompensation there was delay (150-270 days) in obtaining a hepatitis E virus serology, which may have resulted in a negative hepatitis E virus IgM at time of testing.Conclusions: 9.1% of patients presenting with abnormal liver tests at a large teaching hospital in south east England have a positive hepatitis E virus serology of whom 42.8% have acute on chronic liver disease. In 16% hepatitis E virus infection is the aetiology for the acute decompensation. This may be an under representation as in >30% of patients with unexplained decompensation there is considerable delay in requesting a hepatitis E virus serology. (C) 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Objectives:To determine what physiological and biochemical factors predict development of bacteremia in nontransplanted patients with acute on chronic liver failure and, on diagnosis of bacteremia, what is the natural history of bacteremic patients versus control subjects (acute on chronic liver failure). Interventions:None. Design:Retrospective analysis of data collected prospectively and entered into a dedicated physiology database. Setting:Specialist liver intensive therapy unit. Patients:Critically ill non-transplanted patients with acute on chronic liver failure admitted between January 2003 and July 2005. Measurements and Main Results:One hundred eighty-four patients were defined with acute on chronic liver failure; 67 (36%) had bacteremia. One hundred seventeen (64%) patients did not (acute on chronic liver failure). Fifty-eight percent of isolates were Gram-negative organisms, 36% were Gram-positives, and 6% fungemia. Median time to first bacteremia was 8 days (range, 3–12 days). On admission (univariate), bacteremic patients had significantly higher Modified End Stage Liver Disease scores (27 vs. 24, p = .037), Acute Physiology and Chronic Health Evaluation II scores (23 vs. 21, p = .049), and greater degrees of encephalopathy (Glasgow Coma Scale score 10 vs. 12, p = .001). During their liver intensive therapy unit course, bacteremic patients had significantly greater requirements for renal replacement therapy (64% vs. 49%, p = .043), mechanical ventilation (88% vs. 68%, p = .002), and a longer median liver intensive therapy unit stay (16 vs. 5 days, p < .001). Survival to hospital discharge was worse in the bacteremic group (25% vs. 56%, p < .001). Multivariate analysis (logistic regression) was performed separately modeling with Acute Physiology and Chronic Health Evaluation II and Modified End Stage Liver Disease. In the first model, Acute Physiology and Chronic Health Evaluation II (odds ratio 1.24) and bacteremia (2.24) were independent predictors of mortality. In the later model, Modified End Stage Liver Disease (odds ratio, 1.06), requirement for renal replacement therapy (3.08), Glasgow Coma Scale (0.72), and bacteremia (2.30) were significant. Both models performed similarly (Modified End Stage Liver Disease area under the receiver operating characteristic curve, 0.864; Acute Physiology and Chronic Health Evaluation II, 0.862). Conclusions:In nontransplanted patients with acute on chronic liver failure, bacteremia was associated with increased severity of illness on admission, greater requirements for organ support, and independently adversely impacted on survival. Higher Acute Physiology and Chronic Health Evaluation II and Modified End Stage Liver Disease scores were also independently predictive of mortality.

Introduction:The incidence of cirrhosis is increasing exponentially and it is projected that there will be a 5 fold increase in demand for liver transplantation in the next 6-10 years.Historically, the perception of cirrhosis with organ dysfunction as having a poor prognosis has fuelled a selffulfilling prophecy with iniquitous access to intensive care (ICU).However, recent data to support this view is lacking.We report the 7 year experience of the outcome, physiological disturbance and resource utilisation of 658 emergency admissions with cirrhosis and organ dysfunction to a specialist liver ICU.Aims and Methods: We prospectively collected and analysed physiological and biochemical variables on day 1/3 of admission.Outcome variables, organ scores [Child Pugh, MELD, SOFA and APACHE II] and number of days requiring vasopressors, ventilation and renal replacement therapy (RRT) were recorded.The Therapeutic Intervention Scoring System (TISS) score, validated as a tool for estimating cost in ICU, was calculated.Results: Alcohol was the most common aetiology (47%) and variceal bleeding the most common reason for admission (35%).51% required inotropes, 72% invasive ventilatory support and 49% RRT.Despite this, ICU admission for many of these patients was not futile, with 55% surviving their ICU stay and 41% surviving to discharge.Variceal bleeders had a 30 day survival of 53% versus 33% with a non-variceal indication for admission (p < 0.0001).19% of survivors subsequently underwent transplantation.Survival was at a significant cost [median cost/patient: £12,403 (4,636-27,283) for a median 7 day admission (3-15)].Admissions with multi-organ failure (MOF) cost significantly more (MOF p < 0.001; RRT p < 0.0001) and had more prolonged lengths of stay (p < 0.0001).RRT was well tolerated and facilitated recovery in 23/59 (39%) patients who were subsequently transplanted.Conclusion: More than 50% of patients admitted as emergencies will survive their ICU stay with the majority surviving to hospital discharge.These data challenge the widely held prejudice that patients with cirrhosis requiring emergency admission to ICU inevitably die.This endorses the establishment of managed clinical care networks and demands the engagement of all levels of critical care and ward-based care models in the treatment of organ dysfunction in cirrhosis.

PURPOSE OF REVIEW:The incidence of cirrhosis is increasing exponentially and is associated with significant morbidity and mortality. This cirrhotic population is prone to infection, which is a frequent precipitant for the development of organ dysfunction; a syndrome often referred to as 'acute-on-chronic' liver failure. Historically, the perception of cirrhosis with organ dysfunction as having a poor prognosis has led to invariably iniquitous access to intensive care. Data to support this view, however, are lacking. RECENT FINDINGS:Acute variceal bleeding is associated with markedly improved survival and warrants organ support in intensive care. Survival correlates directly with the number of organs failing, with sepsis and multiorgan failure resulting in over 90% mortality. The requirement for renal replacement therapy confers a poor prognosis in patients not suitable for liver transplantation. SUMMARY:Admission to intensive care for many patients with cirrhosis is not futile, particularly for those with single organ dysfunction and acute variceal bleeding. It can be extremely challenging to manage patients with organ dysfunction and encephalopathy in a ward environment, and these patients frequently require, and indeed benefit from, augmented levels of care in high-dependency and intensive care environments.

Portopulmonary hypertension (PPHTN) represents a constrictive pulmonary vasculopathy in patients with portal hypertension. Liver transplantation (LT) may be curative and is usually restricted to patients with mild-to-moderate disease severity characterized by a mean pulmonary artery pressure (mPAP < 35 mm Hg). Patients with severe disease (mPAP > 50 mm Hg) are usually excluded from transplantation. We describe a patient with severe PPHTN, initiated on sequential and ultimately combination therapy of prostacyclin, sildenafil, and bosentan (PSB) pretransplantation and continued for 2 years posttransplantation. Peak mPAP on PSB therapy was dramatically reduced from 70 mm Hg to 32 mm Hg pretransplantation, and continued therapy facilitated a further fall in mPAP to 28 mm Hg posttransplantation. The pulmonary vascular resistance index fell from 604 to 291 dyne second(-1) cm(-5). The perioperative mPAP rose to 100 mm Hg following an episode of sepsis and fell with optimization of PSB therapy. In conclusion, this is the first reported patient with severe PPHTN using this combination of vasodilator therapy as a bridge to LT and then as maintenance in the posttransplantation phase. This regimen may enable LT in similar patients in the future, without long-term consequences.

Renal dysfunction is common in patients with end-stage liver disease. Etiological factors include conditions as diverse as acute tubular necrosis, immunoglobulin A nephropathy and hepatorenal syndrome. Current standard tests of renal function, such as measurement of serum urea and creatinine levels, are inaccurate as the synthesis of these markers is affected by the native liver pathology. This article reviews novel markers of renal function and their potential use in patients with liver disease.